The sterile fetal intestine is abruptly colonised by environemental microbes immediately after birth. The main bacterial components early during colonisation are Gram-negative, endotoxin (LPS) producing bacteria. They may contribute to a number of infectious and inflammatory conditions of the newborn gastrointestinal tract. It has been demonstrated that breast-fed newborns have a lower incidence of intestinal infections, intestinal inflammatory conditions, lower incidence of respiratory infections, and, later in life, less allergic diseases. A number of human milk components may explain the protective role, among, others, immunocompetent cells, antibodies transfering pasive immune protection, human milk oligosaccharides, lysozyme, lactoferrin and other factors have been evoked.
Toll receptors, mediating cell signalling in Drosophila, have to be seen in a completely different context. This important family of trans-membrane molecules is primarily involved in morphogenesis, but later in the life of the adult fly its activation induces a defensive response during infections.
The mammalian homologues of the Toll receptor family were discovered recently (Medzhitov R, Janeway C A Jr. Innate immunity: the virtues of a nonclonal system of recognition, Cell (1997) 91: 295-298). Owing to the apparent relationship, the mammalian homologues are called Toll-like receptors (TLR). As Toll and Toll related proteins in the fly, TLR are transmembrane cell-surface proteins that extend into the intracellular domain. The extracellular region (N-terminal end) generally contains multiple leucine-rich repeats (LRR), and, in the known human and Drosophila family members, a top Cys-rich module that presumably is a juxtamembrane spacer. The intracellular (C-terminal end) domains of the mammalian TLR and Drosophila Toll proteins are similar to the one of the well-described Interleukin 1 and 18 receptors (IL-1R and IL-18R), which indicates similar mechanisms and participants of downstrem signal transducing. So far a family of about ten mammalian TLRs has been identified.
A lot of research has since been conducted in order to find potential ligands that could activate the TLR-mediated signalling from the extracellular side, and, to determine the intracellular signalling pathway of the activated receptor.
It has become clear that the TLR family members are part of the mammalian innate immune system responsible for recognition of and response to bacteria and bacterial cell wall components.
WO 0075358 is based on the discovery of novel TOLL family members (TOLL nucleic acid family members). It is thought that the TOLL molecules according to the invention are useful as targets for developing modulating agents. Hence, nucleotide and amino acid sequences are disclosed and claimed. FIG. 1 of WO 0075358 shows the nucleotide sequence of the human TOLL protein as well as the amino acid sequence encoded therewith. This TOLL protein may be membrane proteins, which function as receptors, and they may be involved in immune signalling mechanisms.
WO 0024776 discloses a novel molecular species TLR6 which belongs to the Toll family. Hence, TLR6 regulates the expression of various genes participating in immune response. Also a gene encoding the receptor is given.
Besides the scientific research, no technically exploitable effect and no other functioning that the ones described above has been disclosed so far.
Consequently, a problem of the present invention is to provide a means of administering an active substance to an individual, whereby the substance will regulate the activatory pathways induced by bacterial products as mediated through components of TLRs, and more specifically TLR-2.